Recent evidence from our group and others has suggested that exposure to polychlorinated biphenyls[unreadable] (PCBs) can cause metabolic oxidative stress in mammalian cells contributing to cell injury and the biological[unreadable] effects of PCBs. Chronic metabolic oxidative stress has also been strongly implicated in degenerative[unreadable] diseases associated with genomic instability, carcinogenesis, and aging.PCB exposure has also been[unreadable] implicated in increased the risk of prostate and breast cancer. Project 2 will investigate the involvement of[unreadable] metabolic oxidative stress in mechanisms of injury and growth disturbances seen in human prostate and[unreadable] breast epithelial cells during PCB exposure. Preliminary results show that exposure of prostate epithelial[unreadable] cells (PrECB) and breast epithelial cells (MCF10A) to PCBs and PCB metabolites cause increased[unreadable] superoxide production and disruptions in glutathione metabolism consistent with induction of metabolic[unreadable] oxidative stress as well as perturbations in cell growth. Specifically the current proposal will test the[unreadable] hypothesis that mitochondria! production of reactive oxygen species (ROS; i.e., superoxide and hydrogen[unreadable] peroxide) causes oxidative stress during PCB exposure and this increased production of ROS contributes to[unreadable] the biological effects of PCBs on cell growth in prostate and breast epithelial cells. Aim#1 will determine if[unreadable] exposure to PCBs or PCB metabolites induces oxidative stress in prostate and breast epithelial cells that[unreadable] contributes to PCB-induced alterations in cell proliferation and cytotoxicity. Aim#2 will determine which[unreadable] specific ROS (i.e., superoxide, hydrogen peroxide, and organic hydroperoxides) and sites of production[unreadable] contribute to oxidative stress and PCB-induced growth disturbances and cytotoxicity in prostate and breast[unreadable] epithelial cells. Aim#3 will determine if manipulation of intracellular thiols or selenium supplementation can[unreadable] modify PCB-induced oxidative stress and growth disturbances in human prostate and breast epithelial cells.[unreadable] The long-term goal of these studies is to provide a rigorous mechanistic understanding of the involvement of[unreadable] metabolic oxidative stress in PCB-induced effects on prostate and breast epithelial cell growth that may[unreadable] contribute carcinogenesis and identify manipulations of antioxidant mechanisms that can protect human[unreadable] prostate and breast epithelial cells from PCB exposure.